Method of inducing central nervous system stimulation



United States Patent 3,258,399 METHOD OF INDUCING CENTRAL NERVOUS SYSTEMSTIMULATION Claude I. Judd, Mequon, and Alexander E. Drukker, Milwaukee,Wis., assignors to Colgate-Palmolive Company, New Y ork, N.Y., acorporation of Delaware No Drawing. Original application Sept. 13, 1962,Ser. No. 223,530. Divided and this application Apr. 22, 1963, Ser. No.278,507

4 Claims. (Cl. 167-65) This application is a divisional of Serial Number223,- 530, filed September 13, 1962.

This invention relates to novel chemical compounds and processes ofpreparing the same. More particularly, this invention is concerned withnovel basic dibenzsuberane derivatives, processes of producing suchcompounds and pharmaceutical uses therefor.

According to the present invention there are provided novel basic10,1l-dihydro-SH-dibenzo[a,d]cycloheptene derivatives of the formula andnontoxic pharmaceutically acceptable acid addition salts thereof,wherein X is hydrogen, chlorine or trifluoromethyl, Y is a straight orbranched chain lower alkylene, advisably of 2 to 4 carbons, such asethylene, propylene, isopropylene and butylene, and R is a straight orbranched chain lower alkyl, advisably of 1 to 3 carbons, such as methyl,ethyl, propyl and isopropyl.

One of method of producing these compounds is to react a5-(N-alkyl-N-benzylaminoalkyl)-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene with a chloroformate to produce anintermediate S-(N-alkyl-N-substituted carboxy-aminoalkyl) 10,11 dihydro5H dibenzo[a,d]- cycloheptene which upon hydrolysis yieldsS-(N-alkylaminoalkyl) 10,11 dihydro 5H dibenzo[a,d]cycloheptene. Thisprocess can be represented as follows:

wherein Ph is phenyl, A is oxygen or sulfur, R is a lower alkyl such asmethyl, ethyl and propyl or phenyl and R, Y and X have the previouslyassigned meaning. The J. Org. Chem. 26, 4057 (1961), illustrates relatedapplications of this process.

3,258,399 Patented June 28, 1966 Some of the starting materials whichcan be used in the process are 5-(3-1N-methy1-N-benzy1amino)propy1-10,ll-dihydro- SH-dib enzo [a,d] cycloheptene,

3-chloro-5- 3-N-methyl-N-benzylamino)propyl- 10,1 1-

dihydro-SH-dibenzo [a,d] cycloheptene,

5- (Z-N-ethyl-N-benzylamino)ethyl-10,1l-dihydro-SH- dibenzo[a,d]cycloheptene and5-(S-N-methyl-N-benzylamino)butyl-lO,1l-dihydro-SH- dibenzo [a,d]cycloheptene.

Among the chloroformates which can be used in the first step of theprocess are methyl chloroformate, ethyl chloroformate, phenylchloroformate, methylthiachloroformate, ethylthiachlorofiorma-te andphenylthiachloroformate.

The debenzylation reaction is readily eifected by bringing the reactantstogether in a suitable inert solvent at from about room temperature toabout 200 C. Benzene is a particularly useful reaction medium and withit a reaction temperature of about C. is suitable. Preferably, thereaction mixture is refluxed for about 5 to 20 hours before reaction isterminated. The intermediate carbamate is isolated from the reactionmixture by conventional methods.

Some of the intermediates produced in this way are 5- (3-N-methyl-N-carbethoxyamino propyl-10,1 l-dihydro-SH-dibenzo [a,d]cycloheptene,

3-ch1oro-5- (Z-N-ethyl-N-carbomethoxyamino ethyl- 10,

1l-dihydro-SH-dibenzo[a,d]cycloheptene,

5- (3 -N-propyl-N-phenoxycarbonylamino)-butyl-10,1 1-

dihydro-SH-dibenzo a,d] cycloheptene and5-(3-N-methyl-N-ethylthiacarbonyl)propyl-10,1 l-dihydro-SH-dibenzo [a,d]cycloheptene.

5-(3-N-methylamino)propyl-10, l l-dihydro-SH-dibenzoa,d]cycloheptene,

3-chloro-5-(3-N-ethylamino)propyl-10,1 l-dihydro-SH- dibenzo[a,d]cycloheptene,

5-(2-N-propylamino)ethyl-lO,1l-dihydro-SH-dibenzo- [a,d] cyclohepteneand 5- (3-N-methylamino) butyl-10,1 l-dihydro-SH-dibenzo- [a,d]cycloheptene.

The compounds of this invention can also be produced by catalyticdebenzylation of a 5(N-alkyl-Nbenzylaminoalkyl) 10,11 dihydro 5Hdibenzo[a,d] cycloheptene to form the 5 (N -alky1aminoalkyl) 10,11-dihydro-5H-dibenzo[a,d] cycloheptene. This process can be represented asfollows:

- wherein Ph, X, Y and R have the assigned meaning.

The catalytic hydrogenation can be accomplished by adding a (N alkyl Nbenzylaminoalkyl) 10,11- dihydro 5H dibenzo[a,d]cycloheptene, preferablyas an acid addition salt such as the hydrochloride, to a suitablesolvent such as water or a lower alcohol. Platinum, platinum oxide andpalladium are catalysts which are useful in efiecting the hydrogenation.Hydrogen pressures of about 30 to 3,000 p.s.i.' and from roomtemperature to moderately elevated temperatures (100 C.) are suitablefor effecting the reaction. The hydrogenation'proceeds quickly and itsprogress can be measured by the hydrogen uptake. ceases the reaction maybe considered completed. After filtering the reaction mixture, it may beevaporated to dryness and the product triturated with a solvent such asether and separated by filtration.

When the hydrogen uptake 5 The compounds of this invention can also beproduced by catalytic reduction, using the conditions just described, of5 (N alkyl N benzylaminoalkylidene) 10,11- dihydro 5Hdibenzo[a,d]cycloheptenes of the formula and 5 (N alkyl Nbenzylaminoalkylidene) 5H- dibenzo[a,d] cycloheptenes of the formulawherein X, R and Ph have the previously assigned meaning and B is astraight or branched lower alkylene of 1 to 5 atoms, and advisably of 1to 3 carbons.

Each of these reductions can be specifically illustrated as follows:

CHC HiC HiN CH CHiCHaC HIN CHCHzCHzN CHzPh H wherein Ph is phenyl.

The compounds of this invention form Water soluble acid addition saltswith organic and inorganic acids such as hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethanedisulphonic acid, acetic acid, citric acid, rnaleic acid, succinic acid,tartaric acid, benzoic acid and phthalic acid.

Since the compounds form acid addition salts, they can be used asneutralizing agents.

The compounds of this invention, as the free bases and nontoxic acidaddition salts thereof, are powerful central nervous system stimulantsin animals. This activity is very unexpected in view of publications byWinthrop et al. in J. Org. Chem. 27, 230 (1962), Protiva et al. in J.Med. Pharm. Chem. 4, 411 (1961), Villani et al. in J. Med. Pharm. Chem.5, 373 (1962), and Engelhardt et al. in Abstract No. 7 of the Divisionof Medicinal Chemistry, A.C.S. Meeting in Washington, 1962, which reportgreatly reduced central activity or total loss of central activity in5-substituted-SH-dibenzo[a,d]cycloheptanes and cycloheptenes lackingexocyclic unsaturation at the S-car-bon atom of the ring.

The compounds provided by this invention can be administered to animals'as pure compounds or in the form of nontoxic acid addition salts. Toobtain a practical size to dosage relationship one or more of thecompounds is usually combined with a suitable pharmaceutical carrier andmade into unit-dosage forms.

Pharmaceutical carriers which are liquid or solid can be used. Thepreferred liquid carrier is water. Flavoring materials can be includedin the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar and talc can be usedto form powders. The powders can be used as such or be tableted, or beused to fill gelatin capsules. Suitable lubricants like magnesiumstearate, binders such as gelatin and disintegrating agents like sodiumcarbonate in combination with citric acid can be used to form thetablets.

Unit dosage forms such as tablets and capsules can contain any suitablepredetermined amount of one or more of the compounds and can beadministered one or more at a time at regular-intervals. Such formsshould, however, contain a concentration of about 0.1 to 10 by weight ofthe compound of this invention.

A typical tablet can have the composition:

(1) 5 N (3 N methylami-no)propyl 10,11dihydro-5H-dibenzo[a,b]cycloheptene HCl 25 (2) Starch, U.S.P 57 (3)Lactose, U.S.P. 73 (4) Talc, U.S.P. 9 (5) Stearic acid 6 Powders 1, 2and 3 are slugged, then granulated, mixed with 4 and 5, and tableted.

Daily administratiion of about 5 to 500 mg. of 5-N-(3-N-methylamino)propyl 10,11 dihydro 5H dibenzo [a,d]cycloheptene HCl andother compounds of this invention is usually satisfactory. However,since some variation between compounds is to be expected, the precisedosages of each is to be evaluated prior to administration. Furthermore,the differences in patients normally will require prescription ofvarious amounts of the active drugs from case to case. In general, theindicated treatment of depressives is about 5 to mg. of the activecompounds given orally periodically during the day in unit dosages ofabout 25 to 50 mg. given three times a day.

The following examples are presented to illustrate the preparation ofrepresentative compounds within the scope of the invention.

EXAMPLE 1 5-(3-N-methyl-N -carbeth0xyamino) propyl-I 0,1 1dihydro-SH-dibenzo [a,d] cycloheptene 'in benzene, extracted with diluteaqueous hydrochloric acid, the aqueous layers were made alkaline withpotassium hydroxide, extracted with ether, dried, filtered andconcentrated. The residue of 5-(3-N-methyl-N-benzylamino) propyl 10,11dihydro 5H dibenzo[a,d] cyclo heptene was distilled to give 12.85 g. ofproduct, B.P. 205 C. (0.08 mm.).

A solution of 10.5 g. (0.0296 mole) of 5-(3-N-methyl- Nbenzylamino)propyl 10,11 dihydro 5H dibenzo [a,d]cycloheptene and 3.8 g.(0.035 mole) of ethylchloroformate in 25 cc. of benzene was refluxed for24 hours. The solution was distilled with steam, the residue dissolvedin benzene, the solution washed with dilute hydrochloric acid and water,dried, filtered and concentrated. The residue was distilled to give 7.8g. of 5-(3- N methyl N carbethoxyamino)propyl 10,11dihydro-SH-dibenzo[a,d]cyc1oheptene, B.P. 214 C. (0.5 mm.).

Analysis.Calcd. for C H NO C, 78.30; H, 8.07 N, 4.15. Found: C, 78.32;H, 8.04; N, 4.32.

EXAMPLE 2 5-(3-N-methylamino)pr0pyl-10,11-dihydr0-5H- dibenz[a,d]cycloheptene A solution of 6.95 g. (0.0206 mole) of -(3-N-methyl- Ncarbethoxyamino)propyl 10,11 dihydro 5H dibezo[a,d]cycloheptene and 10.5g. of barium hydroxide-8H O in 77.5 cc. of ethylene glycol was stirredand refluxed for 10 hours, cooled, and poured into water. The solid wasremoved by filtration and both solid and filtrate were extracted withbenzene. The combined benzene extracts were extracted with dilutehydrochloric acid, the aqueous extracts were made alkaline withpotassium hydroxide, followed by extraction with ether. The etherealextracts were dried over potassium carbonate, filtered and concentratedto leave 3.75 g. of base. The base was converted to the hydrochloride,and this salt was recrystallized from a mixture of equal amounts ofethanol and diethyl ether. M.P. of the HCl salt: 180 C.

Analysis.Calcd. for C H ClN: C, 75.60; H, 8.01; N, 4.64. Found: C,75.55; H, 7.96; N, 4.64.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. The method of inducing central nervous system stimulation in ananimal which comprises the step of orally administering to an animal asmall, safe and effective amount of a member of the group consisting ofcompounds of the formula and nontoxic pharmaceutically acceptable acidaddition salts thereof, wherein X is a member of the group consisting ofhydrogen, chlorine and trifluoromethyl, Y is lower alkylene and R islower alkyl. 5 2. The method of inducing central nervous systemstimulation in an animal which comprises the steps of orallyadministering to an animal a small, safe and effective amount of5-(3-N-methylamino)propyl-lO,1l-dihydro-SH-dibenzo[a,d]cycloheptene.

3. A unit dosage pharmaceutical composition comprising 5 to 150 mg. of amember of the group consisting of compounds of the formula X Y Y-N andnontoxic pharmaceutically acceptable acid addition 25 salts thereof,wherein X is a member of the group consisting of hydrogen, chlorine andtrifiuoromethyl, Y is lower alkylene and R is lower alkyl, and apharmaceutical carrier.

4. A unit dosage pharmaceutical composition comprising 5 to 150 mgm. of5-(3-N-methylamino)propyl-10,11- dihydro-5I-I-dibenzo[a,d]cycloheptene,and a pharmaceutical carrier.

References Cited by the Examiner FOREIGN PATENTS 613,363 8/1962 Belgium.858,188 1/1961 Great Britain.

OTHER REFERENCES Protiva et al.: Journal of Med. and Phar. Chem., v01.4, No. 2, pp. 411-15 (1961).

JULIAN S. LEVITT, Primary Examiner. S. FRIEDMAN, N. MANN, AssistantExaminers.

1. THE METHOD OF INDUCING CENTRAL NERVOUS SYSTEM STIMULATION IN ANANIMAL WHICH COMPRISES THE STEP OF ORALLY ADMINISTERING TO AN ANIMAL ASMALL, SAFE AND EFFECTIVE AMOUNT OF A MEMBER OF THE GROUP CONSISTING OFCOMPOUNDS OF THE FORMULA